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Almost all people with genotype 1 hepatitis C who were
previously unsuccessfully treated with a course of interferon-free
direct-acting antiviral therapy achieved sustained response when retreated with
a three-drug combination being developed by Merck, researchers reported at the International
Liver Congress last week in Amsterdam.

Direct-acting antivirals (DAAs) have revolutionised
the treatment of chronic hepatitis C virus (HCV) infection, with cure rates
approaching 100% for most groups of patients. But better options are still
needed for people who do not respond to a first attempt at interferon-free
therapy and may have drug-resistant virus.

Heiner Wedemeyer of Hannover Medical School in
Germany presented findings from the phase 2 C-SURGE trial, which evaluated a once-daily
coformulation of grazoprevir, uprifosbuvir and ruzasvir in people who
relapsed after treatment with a DAA regimen containing an HCV NS5A inhibitor.

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness.

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

A building block of DNA or RNA, chemical structures that store genetic information.

Attacking HCV at multiple different targets has a better
chance of overcoming resistance and maintaining viral suppression. Grazoprevir is
an HCV NS3 protease inhibitor, uprifosbuvir (formerly MK-3682) is a nucleotide NS5B polymerase
inhibitor, and ruzasvir is an NS5A inhibitor. This combination previously demonstrated cure rates over 90% for people new
to treatment and those with prior interferon-based therapy failure.

C-SURGE included 94 participants with HCV genotype 1,
mostly harder-to-treat subtype 1a. Most (80%) were men and the median age was
60 years. More than 40% had compensated cirrhosis; people with decompensated
liver disease were excluded.

Just over 60% were previously treated with
sofosbuvir/ledipasvir (Harvoni) for
at least 12 weeks, 15% had taken Harvoni
for only 8 weeks, which is shorter than the recommended treatment duration, and
24% had used grazoprevir/elbasvir (Zepatier)
for 12 weeks – that is, they had already used one of the drugs in the new coformulation.

Most participants had evidence of DAA resistance at
baseline. Over 80% had virus with NS5A resistance-associated substitutions
(RASs); 41% had one, 39% had two and 4% had three or more of these RASs. About
two-thirds (65%) had NS3 protease RASs and 55% had both NS5A and NS3 resistance.

Participants in this open-label study were randomly
assigned to receive once-daily grazoprevir/uprifosbuvir/ruzasvir (100/450/60mg)
either with ribavirin for 16 weeks or without ribavirin for 24 weeks. The primary
study endpoint was sustained virological response, or undetectable HCV RNA 12
weeks after the end of treatment (SVR12).

Cure rates were 98% using the 16-week regimen and 100% using the
24-week regimen in an intent-to-treat analysis. The single individual in the
16-week arm who did not achieve SVR12 left the study after taking only three
doses of medication. The presence of
cirrhosis and resistance-associated substitutions – including the Y93 NS5A RAS
– had no effect on treatment outcomes.

Treatment was generally safe and well tolerated. There
were no drug-related serious adverse events or discontinuations due to adverse
events. The most common events were fatigue, headache, diarrhoea, rash and
itching, mostly mild or moderate. Four people who used ribavirin (9%) developed
anaemia.

Editors’ picks from other sources

Welcome to the 2019 Pipeline Report. Our annual review provides an overview of research and development of innovations for diagnosing, preventing, treating, and curing HIV, hepatitis C virus (HCV), and tuberculosis (TB).

Welcome to the 2018 Pipeline Report, Treatment Action Group’s annual review of therapeutics, diagnostics, vaccines, and preventive technologies in development for HIV, hepatitis C virus (HCV), and tuberculosis, along with immune-based and gene therapies and research toward a cure for HIV.

Slowing hepatitis C drug sales have taken a bite out of Gilead's share price.This is a smart retreat for Merck and J&J. The HCV market is well past its peak. Both of their new therapies would have been very late; AbbVie and Gilead both had new drugs approved this year. Their best hope likely would have been to compete on price in a market that's been warring over price for a while.

The FDA recently approved two new combination regimens for hepatitis C, raising the question of whether further drug development is warranted in this area. Experts agree, however, that more remains to be done in terms of implementation: getting everyone at risk screened for HCV infection, and getting those who test positive on effective treatment.

Janssen Sciences Ireland UC, a unit of Johnson & Johnson, said it would discontinue further development of its hepatitis C research, citing increased availability of a number of effective hepatitis C therapies.

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